The present invention relates to 4,5-oxazole derivatives and analogs thereof, pharmaceutical compositions containing them and methods of using them to treat inflammation and/or pain in mammals. More particularly, this invention relates to selected 2-substituted-4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazoles or 2-substituted-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)oxazoles having antiinflammatory and/or analgesic activity without erosion of the stomach.
2,3-Diaryl-5-halo thiophenes are disclosed in U.S. Pat. No. 4,590,205 as analgesic or antiinflammatory agents. More particularly, 2,3-diaryl-5-bromo thiophenes are disclosed in U.S. Pat. No. 4,820,827 as having unexpected antiinflammatory and prostaglandin synthetase inhibitory activity for use in the treatment of inflammation and dysmenorrhea. Copending application U.S. Ser. No. 08/004,822 discloses 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiophene and its 2-substituted bromo analog among its preferred compounds for antiinflammatory activity.
WO/91/19708 discloses thiophenes having various 5-substituents, as well as, 2,3-substitutions having antiinflammatory activity.
U.S. Pat. No. 3,743,656 and U.S. Pat. No. 3,644,399, which is the parent of U.S. Pat. No. 3,743,656, disclose more generically both thiophene and furane derivatives having antiinflammatory activity.
Preparation of a wide-variety of asymmetric biaryl compounds including substituted thiophene, furane and pyrrol rings is disclosed in U.S. Pat. No. 4,990,647 having a suggested utility as precursors for brighteners, pharmaceuticals, plant protection active compounds and liquid crystal materials.
Pyrazole derivatives having antiinflammatory activity are disclosed in European Patent Application Number 90117983.8.
Agents for the treatment of hypertension are disclosed as alkyl-arylimidazole, thiazole and oxazole derivatives in U.S. Pat. No. 4,632,930.
More specifically, U.S. Pat. No. 3,578,671 discloses oxazoles substituted in the 2-position by a saturated or unsaturated aliphatic acid and having 4 and 5 substituents, including phenyl which may be further substituted. French 2156486 of Derwent Abstract No. 41925U-B and U.S. Pat. No. 4,051,250 both generically disclose compounds including 2-oxazolylmercaptoalkanoic acid (esters, amides or cyano derivatives) ring systems having 4,5-diaryl groups which are phenyls both unsubstituted or substituted by a wide variety of substituents and having antiphlogistic, analgesic and antipyretic activity, particularly useful for treating arthritis.
Diarylheterocycles are disclosed in CA114(5):42807w for use as drugs including use against rheumatic and arthritic diseases.
Other related disclosures include U.S. Pat. No. 4,001,228 for antiaggregating activity and U.S. Pat. No. 3,895,024 for intermediates in the production of antiinflammatory agents.
U.S. Pat. No. 4,489,084 describes oxazolyl (or thiazolyl) hydrazinoalkyl nitrile compounds having including two phenyl substituents which phenyls are also further substituted for use as antiinflammatory agents. U.S. Pat. No. 4,143,047 entitled "2-Sulfinyl and 2Sulfonyl Oxazoles" discloses such compounds as reactants to make 2-acylamino oxazole derivatives having antiallergic activity.
Additionally, German Patent No. 3030661 described in Derwent Abstract No. 26458 E/14 provides heteroarylpropargyl ethers as synergists in pesticides, EP 402-246A described in Derwent Abstract 90-370247/50 provides azolyl-substituted alkoxy-acrylate derivatives for use as fungicides and Japanese Patent No. 3014-562 A described in Derwent Abstract No. 91-067958/10 provides alkylene diamine derivatives useful as glutamic acid blockers.
The above references, that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel oxazoles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts.
The invention compounds are found to show usefulness in vivo as antiinflammatory agents, particularly as antiarthritic agents without ulcerogenic side effects.